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1.
Glutathione S-transferase M1 and T1 and cytochrome P4501A1 polymorphisms in relation to the risk for benign and malignant head and neck lesions 总被引:1,自引:0,他引:1
MB Oude Ophuis EM van Lieshout HM Roelofs WH Peters JJ Manni 《Canadian Metallurgical Quarterly》1998,82(5):936-943
BACKGROUND: Susceptibility to head and neck cancer in a particular individual may depend in part on the metabolic balance between Phase 1 enzymes, such as cytochromes P450 (CYPs), and Phase II enzymes, such as glutathione S-transferases (GSTs). Genetic variability in CYP and GST isoenzymes may contribute to individual differences in susceptibility to chemical carcinogenesis. GSTM1 and GSTT1 null genotypes as well as polymorphic variants in the CYP1A1 gene that may help determine the risk for head and neck cancer have been described in previous reports. METHODS: Polymorphisms of GSTM1, GSTT1, and CYP1A1 in whole blood were detected by polymerase chain reaction (PCR) in 185 patients with head and neck squamous cell carcinoma (HNSCC), 78 patients with benign head and neck lesions (BHNL), and 207 blood donors. RESULTS: GSTM1 null genotype was demonstrated to be equally frequent in patients with HNSCC (50.8%), patients with BHNL (47.4%), and blood donors (51.7%). GSTT1 null genotype occurred significantly more often in patients with BHNL (33.3%) as compared with blood donors (20.3%), demonstrating that lack of GSTT1 may be a risk factor for BHNL. Presence of the rare valine in the CYP1A1/Nco1 site was found in 33 patients with HNSCC (17.8%), in 20 patients with BHNL (25.6%), and in 34 blood donors (16.4%). The frequencies with which the presence of the rare cytosine nucleotide in the CYP1A1/Msp1 site was detected were 17.8%, 15.4%, and 15.9%, respectively. CONCLUSIONS: The occurrence of polymorphic variants in the GSTM1, GSTT1, and CYP1A1 genes did not differ between the groups investigated, therefore indicating no significant contribution to the development of head and neck cancer. 相似文献
2.
S Landi H Norppa G Frenzilli G Cipollini I Ponzanelli R Barale A Hirvonen 《Canadian Metallurgical Quarterly》1998,8(6):461-471
Although some blood parameters have been suggested to modulate in-vitro induction of sister chromatid exchanges by 1,2:3,4-diepoxybutane (DEB), a metabolite of 1,3-butadiene, the increased sensitivity has largely been assigned to a homozygous deletion of glutathione S-transferase T1 gene (GSTT1 null genotype). However, some DEB-sensitive individuals have been shown to be GSTT1 positive (having at least one undeleted GSTT1 allele). To examine potential causes for this overlap, we evaluated the effect of GSTM1, GSTP1, and GSTT1 genotypes, together with various life-style and blood parameters, on the DEB induction of sister chromatid exchanges and cells with chromosomal aberrations (aberrant cells) in lymphocyte cultures of 115 and 62 human donors, respectively. Our results supported the important role of the GSTT1 genotype in DEB sensitivity; 76% of cultures from GSTT1 null donors but only 4% of those from GSTT1 positive donors were DEB-sensitive, as defined by sister chromatid exchange measurements. The GSTT1 genotype also clearly affected DEB-induced aberrant cells, 92% of GSTT1 null and 8% of GSTT1 positive donors being sensitive to DEB. All individuals showing a high response to DEB in both sister chromatid exchange and aberrant cell analyses were GSTT1 null. Baseline aberrant cell measurements but not sister chromatid exchange measurements were marginally higher among GSTT1 null donors compared with GSTT1 positive donors. GSTM1 and GSTP1 genotypes had no influence on these cytogenetic end-points. Blood transaminases, gamma-glutamyl transferase, urea, creatinine and white blood cell count showed a clear negative association with DEB-induced aberrant cells, whereas wine drinkers had more aberrant cells than non-drinkers. A higher sister chromatid exchange-response to DEB was observed in lymphocytes from women and smokers than from men and non-smokers, respectively. Erythrocyte count correlated negatively with DEB-induced sister chromatid exchanges. Thus, a variety of parameters seemed to modulate the individual DEB-sensitivity together with the GSTT1 genotype. Although the known contributing factors accounted for a considerable part of individual variability in sister chromatid exchanges (59.4%) and aberrant cells (46.7%) in DEB treatment, they did not, however, fully explain the overlap in cytogenetic response between GSTT1 positive and null individuals. 相似文献
3.
CL Chen Q Liu CH Pui GK Rivera JT Sandlund R Ribeiro WE Evans MV Relling 《Canadian Metallurgical Quarterly》1997,89(5):1701-1707
The genetic polymorphisms in human glutathione S-transferases (GST) M1 and T1 have been associated with race, disease risk, and outcome of some adult cancers. Also, there are racial differences in the incidence and characteristics of childhood acute lymphoblastic leukemia (ALL). Our objectives were to compare the frequency of the null genotype for GSTM1, GSTT1, or both in children with ALL to that in healthy controls, and to determine whether GST genotype was associated with treatment outcome and prognostic factors. We studied GSTM1 and GSTT1 genotypes in somatic cell DNA from black children and white children with ALL and in 416 healthy controls, using a polymerase chain reaction technique. Ninety of 163 (55.2%) white ALL patients and 14 of 34 (41.2%) black patients were GSTM1 null, frequencies not significantly different (P = .19) than healthy controls (53.5% in whites and 27.6% in blacks), although there was a trend toward more null genotypes in black ALL patients. Twenty-three of 163 (14.1%) white ALL patients and 12 of 34 (35.3%) black ALL patients were GSTT1 null, not different (P = .34) than the frequencies in healthy controls (15.0% in whites and 24.1% in blacks). However, the frequency of the "double-null" genotype, lacking both GSTM1 and GSTT1, was higher in black patients with ALL (8 of 34 or 23.5%) than in black controls (3.9%) (P = .0005), but this was not the case in white patients with ALL (10 of 163 or 6.1%) compared to white controls (8.0%) (P = .68). In stratified analyses, the GST double-null genotype was not associated with other characteristics that might differ between whites and blacks with ALL, such as age, T-lineage immunophenotype, presenting white blood cell count, DNA index, or insurance status. The null genotype for GSTM1, GSTT1, or both was not found to be a prognostic factor for disease-free survival or probability of hematologic remission; central nervous system relapse tended to be less common in those with the GSTM1 null genotype (P = .054). The double-null genotype for GSTM1 and GSTT1 is more common among blacks but not whites with childhood ALL. These data suggest that GST genotype, coupled with unidentified additional risk factors, may play a role in risk of childhood ALL in American blacks. 相似文献
4.
EM van Lieshout HM Roelofs S Dekker CJ Mulder T Wobbes JB Jansen WH Peters 《Canadian Metallurgical Quarterly》1999,59(3):586-589
Factors determining individual susceptibility to esophageal cancer or premalignant Barrett's epithelium are still largely unclear. An imbalance between phase I drug metabolism [e.g., cytochrome P450 (CYP)] and phase II detoxification [e.g., glutathione S-transferase (GST)] may contribute to the development of these diseases. Polymorphic variants in the CYP1A1 gene were described leading to increased levels of bioactive compounds, whereas polymorphisms in GST genes often resulted in impaired detoxification. We studied the frequencies of polymorphic variants in CYP1A1, GSTP1, GSTT1, and GSTM1 genes in 98 patients with Barrett's epithelium and 34 patients with esophageal cancer. The results were compared with those obtained from 247 healthy blood donors. DNA was extracted, and PCR-RFLP methods were used to detect genetic polymorphisms. Chi2 analysis, Spearman rank correlation, and Wilcoxon rank sum tests were used for statistical evaluation. Polymorphisms in CYP1A1, GSTM1, and GSTT1 occurred at an equal frequency in patients and controls. Occurrence of the polymorphic GSTP1b variant in the GSTP1 gene resulted in a significantly lower GST enzyme activity (P < 0.05), and GSTP1b was found significantly more often in patients with Barrett's epithelium (70%; P < 0.001) and patients with esophageal adenocarcinoma (76%; P = 0.005), as compared to healthy blood donors (41%). In conclusion, presence of the GSTP1b allele leads to lower GST enzyme activity levels and, consequently, impaired detoxification. This most important esophageal GST isoform may, therefore, contribute to the development of Barrett's epithelium and adenocarcinoma. 相似文献
5.
A combined analysis of two polymorphic enzymes, glutathione S-transferase mu (GST M1) and q (GST T1) and their implication as cancer risk factors was performed in a case-control study of lung and bladder cancers. Using a multiplex polymerase chain reaction (PCR) based method, the frequency of the homozygous deleted GSTM1 and GSTT1 genotypes was examined in 117 lung cancer patients, 67 urinary bladder cancer patients, and in a community-based sample of 248 healthy, unrelated individuals. In both cancer groups the frequency of the GSTM1 null genotype was higher in comparison with that of the control group (59% and 59.7% vs. 49.6%), but this increase did not reach statistical significance (p > 0.05). After grouping by the smoking status, among smokers in both cancer groups (62.1% in lung cancer and 71.4% in the bladder cancer group, respectively) there were statistically significantly (p < 0.05) increased frequencies of the GSTM1 deletion genotype as compared to the control group (49.6%). Smokers with absence of the GSTM1 gene were at an approximately 1.7-fold higher risk for lung cancer (odds ratio--OR = 1.67, 95% confidence interval--CI 95% = 1.0-2.7, p = 0.04) and an approximately 2.5-fold higher risk for bladder cancer (OR = 2.54, CI 95% = 1.2-5.5, p = 0.02). As related to GSTT1, our study demonstrated an overall GSTT1 effect on bladder cancer risk. Individuals with absence of the GSTT1 gene were at an approximately 2.5-fold higher risk of developing bladder cancer. In the lung cancer cases, the frequency of the putatively high risk GSTT1 null genotype was not increased as compared with controls. No effect of smoking was found on risk of lung and bladder cancer associated with the GSTT1 0/0 genotype. In combined analysis, the obtained results suggested that individuals who were both GSTM1 null and GSTT1 null may be at increased risk because they lack both enzymes. The findings suggest that the GSTM1 null genotype may be associated with susceptibility to lung and urinary bladder cancer in dependence on the exposure to carcinogens in cigarette smoke and that the GSTT1 null genotype is not a critical factor in mediating the risk of lung cancer, but may be associated with an increased susceptibility to bladder cancer. 相似文献
6.
DX Lin YM Tang Q Peng SX Lu CB Ambrosone FF Kadlubar 《Canadian Metallurgical Quarterly》1998,7(11):1013-1018
Genetic polymorphisms in enzymes involved in carcinogen metabolism have been shown to influence susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for the bioactivation of many low molecular weight carcinogens, including certain nitrosamines, whereas glutathione S-transferases (GSTs) are involved in detoxifying many other carcinogenic electrophiles. Esophageal cancer, which is prevalent in China, is hypothesized to be related to environmental nitrosamine exposure. Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility. DNA samples were isolated from surgically removed esophageal tissues or scraped esophageal epithelium from cases with cancer (n = 45), cases with severe epithelial hyperplasia (n = 45), and normal controls (n = 46) from a high-risk area, Linxian County, China. RFLPs in the CYP2E1 and the GSTP1 genes were determined by PCR amplification followed by digestion with RsaI or DraI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was examined by a multiplex PCR. The CYP2E1 polymorphism detected by RsaI was significantly different between controls (56%) and cases with cancer (20%) or severe epithelial hyperplasia (17%; P < 0.001). Persons without the RsaI variant alleles had more than a 4-6-fold risk of developing severe epithelial hyperplasia (adjusted odds ratio, 6.0; 95% confidence interval, 2.3-16.0) and cancer (adjusted odds ratio, 4.8; 95% confidence interval, 1.8-12.4). Polymorphisms in the GSTs were not associated with increased esophageal cancer risk. These results indicate that CYP2E1 may be a genetic susceptibility factor involved in the early events leading to the development of esophageal cancer. 相似文献
7.
RJ Srám P R?ssner K Peltonen K Podrazilová G Mracková NA Demopoulos G Stephanou D Vlachodimitropoulos F Darroudi AD Tates 《Canadian Metallurgical Quarterly》1998,419(1-3):145-154
The association of occupational exposure to 1,3-butadiene (BD) and induction of cytogenetic damage in peripheral lymphocytes was studied in 19 male workers from a monomer production unit and 19 control subjects from a heat production unit. The exposure to BD was measured by passive personal monitors. The following biomarkers were used: chromosomal aberrations (CA), sister chromatid exchanges (SCE), cells with a high frequency of SCE (HFC), micronuclei, comet assay parameters like tail length (TL) and percentage of DNA in tail [T (%)] and polymorphisms of GSTM1 and GSTT1 genotypes. BD exposure with a median value of 0.53 mg/m3 (range: 0.024-23.0) significantly increased (a) the percentage of cells with chromosomal aberrations in exposed vs. control groups (3.11% vs. 2.03%, P<0.01), (b) the frequency of SCE per cell (6.96 vs. 4.87, P<0.001), and (c) the percentage of HFC (19.9% vs. 4.1%, P<0.001). BD exposure had no significant effects on formation of micronuclei and on comet assay parameters. Effect of smoking was observed only for HFC in BD-exposed group. GSTM1 genotype affected chromosomal aberrations in exposed group, while GSTT1 genotype affected chromosomal aberrations in controls. No effect of GSTM1 or GSTT1 genotypes was observed on any other biomarkers used. 相似文献
8.
GM Stave 《Canadian Metallurgical Quarterly》1996,11(1):79-85
Spontaneous and diepoxybutane (DEB)-induced sister-chromatid exchanges (SCEs) were examined in whole-blood lymphocyte cultures of 3 men and 4 women. A strong increase in mean number of SCEs per cell with increasing DEB concentrations (0, 2, and 4 microM) was observed in cultures of all subjects, but 3 of the donors were clearly more sensitive than the others. The SCE measurements were repeated 2-6 times per donor over a period of 55 months to assess the stability of the individual SCE response. The results showed that SCE induction by DEB was steady in the individuals during the follow-up at each DEB dose, with no significant differences among the repeated experiments. At 4 microM DEB, the DEB-sensitive and -resistant donors could be reliably be differentiated from each other in all trials. As DEB-sensitivity has been suggested to be due to the lack of glutathione S-transferase (GST) T1, the donors were genotyped for the presence of GSTT1 and GSTM1 genes. The 3 individuals found to be DEB-sensitive were all of the GSTT1 null genotype, whereas the 4 DEB-resistant donors were GSTT1 positive, which supported the role of the GSTT1 gene in determining DEB-sensitivity. Three of the DEB-resistant and none of the DEB-sensitive had the GSTM1 null genotype. Thus, the lack of the GSTM1 gene was not associated with the DEB-sensitivity trait. In conclusion, the present findings show that individual SCE responses to treatment of cultured human lymphocytes with DEB can reliably be reproduced in repeated trials. The results confirm that the GSTT1 gene but not the GSTM1 gene is important in determining individual sensitivity to the in vitro genotoxicity of DEB. 相似文献
9.
RE Howells CW Redman KK Dhar P Sarhanis C Musgrove PW Jones J Alldersea AA Fryer PR Hoban RC Strange 《Canadian Metallurgical Quarterly》1998,4(10):2439-2445
Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents. 相似文献
10.
AL Moisio P Sistonen JP Mecklin H J?rvinen P Peltom?ki 《Canadian Metallurgical Quarterly》1998,115(6):1387-1394
BACKGROUND & AIMS: The phenotype of hereditary nonpolyposis colorectal cancer shows interfamilial and intrafamilial variation even in the presence of identical predisposing mutations, suggesting the existence of additional phenotype determinants. The modifying role of genetic polymorphisms in loci involved in carcinogen metabolism was studied. METHODS: We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively). Polymorphisms in N-acetyltransferase 1 (NAT1) and glutathione S-transferase (GST) M1 and GSTT1 were investigated. RESULTS: The NAT1 allele 10 was associated with lower median age at diagnosis in both groups. In mutation 1 group, the NAT1 allele 10 was a risk factor for distal tumor location, both alone (P = 0.028) and combined with the GSTT1-positive genotype (P = 0.008). On the other hand, the combined null genotype of GSTM1 and GSTT1 was associated with proximal tumors. Associations with tumor location were not observed in patients with mutation 2, probably reflecting a small sample size. CONCLUSIONS: The results suggest that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair. 相似文献
11.
S Ozawa 《Canadian Metallurgical Quarterly》1997,117(10-11):895-909
Xenobiotic metabolizing enzymes are known to play a role in the metabolic activation of environmental mutagens and carcinogens to exert their carcinogenic effects as well as detoxification by increasing their hydrophilicity. These enzymes include cytochrome P450s, glutathione S-transferases (GSTs), acetyltransferases (NATs) and sulfotransferases. Genetic polymorphisms in many of these enzymes, such as CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1, GSTP1 and GSTT1, have been shown to occur, which result in the altered expression of enzymatic activities. This suggests that the genetic polymorphisms may affect the individual susceptibility to environmental carcinogens and thus play a role in human carcinogenesis. Recently, the mutations that confer those polymorphisms of xenobiotic metabolizing enzymes have been identified and genotyping methods for the genetic polymorphisms have been developed. Specific phenotypes and genotypes for CYP1A1, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1 and GSTP1 have been associated with susceptibility to malignant diseases including lung, bladder and colon cancers, although the association was not confirmed in some studies. A number of factors such as degree of exposure to environmental carcinogens and the role of xenobiotic metabolizing enzymes in human carcinogenesis should carefully be evaluated in understanding genetic susceptibility. 相似文献
12.
BL Pool-Zobel A Bub UM Liegibel S Treptow-van Lishaut G Rechkemmer 《Canadian Metallurgical Quarterly》1998,7(10):891-899
A previous intervention study had shown that consumption of carotenoid-containing vegetable juices reduces oxidative DNA damage in lymphocytes of 23 male subjects. It was the aim of this study to elucidate the potential mechanisms involved. Specifically, we studied the modulation of protein expression and determined susceptibility factors. Cryopreserved lymphocytes from the study were analyzed for genetic polymorphisms of glutathione S-transferase (GSTM1, GSTP1, and GSTT1) using multiplex PCR, GSTP1-protein with an ELISA, total protein by a colorimetric enzyme reaction, and DNA-repair enzymes with the Comet Assay. Analyses of the genotoxicity data revealed a more steady state of protection for GSTM1*+ than for GSTM1*0 (15 and 8 of 23, respectively) genotypes. Increased expression of cytosolic protein was observed in 11 of 23 subjects, increased expression of GSTP1 in 6 of 23 subjects, and capacity of repair of oxidized DNA bases in 9 of 21 subjects. GSTP1 induction was independent of the GSTP1 genotype (GSTP1a or GSTP1b/c alleles). Kinetics of induction of cytosolic protein and of GSTP1 were compared in one GSTM1*+ and one GSTM1*0 subject and showed an efficacy of tomato and carrots, but not of spinach. Reduced genetic DNA damage in lymphocytes may be due to the enhancement of cytosolic GSTP1, and DNA-repair proteins by tomato and carrot juices. Enhancement of cytosolic proteins may be indicative of increased gene expression by vegetable juices, some of which may be associated with protective activities. 相似文献
13.
A Seow CY Shi FL Chung D Jiao JH Hankin HP Lee GA Coetzee MC Yu 《Canadian Metallurgical Quarterly》1998,7(9):775-781
Isothiocyanates (ITCs), degradation products of glucosinolates (which occur naturally in a variety of cruciferous vegetables), have been shown to exhibit chemopreventive activity. These compounds are metabolized in vivo to form the corresponding dithiocarbamates, which are the major urinary metabolites of ITCs, by a pathway involving the glutathione S-transferase (GST) class of enzymes. Using a newly developed assay that measures total ITC (primarily ITC conjugates) in urine, we examined the relationships between cruciferous vegetable intake (obtained from a food frequency/portion size questionnaire administered in person); dietary total ITC level; GSTM1, GSTT1, and GSTP1 genotypes; and levels of total ITC in spot urine samples collected from 246 Singapore Chinese (111 men and 135 women), ages 45-74 years, who are participants of the Singapore Cohort Study on diet and cancer. Consumption level of cruciferous vegetables was high in study subjects (mean consumption = 345 times per year, mean daily intake = 40.6 g), which was >3 times the comparable level of intake in the United States. Mean daily intake of total ITC among study subjects was 9.1 micromol, and there was a 2.5-fold difference between the 25th and 75th percentile values. Seventy-three % of study subjects tested positive for ITC in urine, and there was a 4-fold difference between the 25th and 75th percentile values among the positive subjects. There was a highly significant positive association between dietary intake and urinary excretion levels of total ITC (two-sided P = 0.0003) that was stronger than the association between overall cruciferous vegetable intake and urinary ITC level, which also was statistically significant (P = 0.0004). There was no difference in urinary ITC levels between GSTM1-null and GSTM1-positive study subjects (P = 0.61) or between subjects with differing GSTP1 genotypes (P = 0.77), but urinary excretion of ITC was significantly higher among GSTT1-positive subjects, relative to GSTT1-null subjects (P = 0.006). The strength of the association between GSTT1 genotype and urinary total ITC level was highly dependent on the level of cruciferous vegetable consumption (or dietary ITC level) in study subjects. Among subjects in the lowest tertile of cruciferous vegetable intake, there was little evidence of an association between GSTT1 genotype and urinary total ITC level (P = 0.67). In contrast, there was a strong and statistically significant association between GSTT1 genotype and urinary total ITC among subjects in the highest tertile of cruciferous vegetable intake (P = 0.02), whereas those in the middle tertile of cruciferous vegetable consumption exhibited an association of intermediate strength (P = 0.04). These results suggest the presence of GSTT1 inducers in cruciferous vegetables. 相似文献
14.
A Menegon PG Board AC Blackburn GD Mellick DG Le Couteur 《Canadian Metallurgical Quarterly》1998,352(9137):1344-1346
BACKGROUND: Parkinson's disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. METHODS: We genotyped by PCR polymorphisms in four GST classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. We asked all patients for information about pesticide exposure. FINDINGS: The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients: AA 14 [54%] of 26 vs seven [18%] of 39; AB 11 [42%] of 26 vs 22 [56%] of 39; BB 1 [4%] of 26 vs six [15%] of 39; AC 0 vs four [10%] of 39, p=0.009). No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. INTERPRETATION: GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides. 相似文献
15.
M Ieko M Kohno A Ohmoto A Notoya Y Fukazawa T Yasukouchi K Sawada T Koike 《Canadian Metallurgical Quarterly》1998,39(7):512-518
BACKGROUND: Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer. METHODS: In 1989, a total of 32 898 individuals donated blood samples to a research specimen bank established in Washington County, MD. Genotypes of blood specimen DNA were determined for 110 of 115 women with incident cases of breast cancer diagnosed during the period from 1990 through 1995 and up to 113 of 115 control subjects. Associations between specific genotypes and the development of breast cancer were examined by use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65). For GSTP1, the data were suggestive of a trend of increasing risk with higher numbers of codon 105 valine alleles (compared with isoleucine alleles); a 1.97-fold increased risk of breast cancer (95% CI = 0.77-5.02) was associated with valine/valine homozygosity. The risk of breast cancer associated with the GSTT1 homozygous null genotype was 1.50 (95 % CI = 0.76-2.95). The risk of breast cancer increased as the number of putative high-risk genotypes increased (P for trend <.001) (OR = 3.77; 95% CI = 1.10-12.88 for a combined genotype of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity). CONCLUSIONS: Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer. 相似文献
16.
R Thier FA Wiebel A Hinkel A Burger T Brüning K Morgenroth T Senge M Wilhelm TG Schulz 《Canadian Metallurgical Quarterly》1998,72(10):622-629
Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results. 相似文献
17.
VS Baranov T Ivaschenko B Bakay M Aseev R Belotserkovskaya H Baranova P Malet J Perriot P Mouraire VN Baskakov GA Savitskyi S Gorbushin SI Deyneka E Michnin A Barchuck V Vakharlovsky G Pavlov VI Shilko T Guembitzkaya L Kovaleva 《Canadian Metallurgical Quarterly》1996,97(4):516-520
A homozygous gene deletion at the glutathione S-transferase M1 (GSTM1) locus of genomic DNA from blood spots was studied by PCR in the group of Slavic populations from the north-western and central-eastern regions of European Russia and in patients with lung cancer (LC), other tumors (OT), endometriosis (E), alcoholic cirrhosis (AC), cystic fibrosis (CF) and chronic bronchitis (CB). The frequencies of the GSTM1 0/0 genotype were 38.8% and 67.5% for both population groups, respectively. The proportion of the GSTM1 gene deletion genotype was estimated as significantly increased in LC (81%), OT (65%), E (81%), AC (77.3%), and in CB (73.6%) patients with symptoms of CB confirmed by X-ray but not in CB patients without X-ray evidence of disease (40.9%). A definite preponderance of GSTM1-0 homozygotes (51.1%) has been registered in CF patients of the pancreatic sufficient group with clear-cut pulmonological manifestations but not in those of the pancreatic insufficient group with predominantly intestinal or mixed clinical symptoms (41.2% and 37.5%, respectively). Earlier clinical manifestations and death before the age of 5 years are typical for GSTM1-deleted CF patients. These data support the notion that GSTM1 deletion should be considered as a convenient genetic marker for the early detection of groups at higher risk of many diseases caused by environmental and genetic factors, where manifestation depends on the lack of detoxification. High levels of GSTM1 0/0 genotypes in E patients favor the substantial contribution of certain environmental toxins in the pathogenesis of this widespread disease. 相似文献
18.
19.
F Nyberg SM Hou K Hemminki B Lambert G Pershagen 《Canadian Metallurgical Quarterly》1998,7(10):875-883
We conducted a case-control study to assess the risk of lung cancer in relation to genetic polymorphisms of the detoxifying enzymes glutathione-S-transferase mu1 (GSTM1) and N-acetyl transferase 2 (NAT2), focusing on never-smokers, women, and older people. The study base consisted of persons > or =30 years of age in Stockholm County from 1992 to 1995. We recruited never-smoking lung cancer cases and a sex- and age-matched sample of ever-smoking cases at the three county hospitals mainly responsible for diagnosing and treating lung cancer. A total of 185 cases (25.4% men; 47.6% never-smokers) and 164 frequency-matched population controls (28.7% men; 48.2% never-smokers) supplied blood for genotyping. Detailed information was collected by interview on active and passive smoking, occupations, residences, and diet. The overall odds ratio (OR) for lung cancer associated with the GSTM1 null (GSTM1-) versus GSTM1+ genotype was 0.8 [95% confidence interval (CI), 0.5-1.2], with an OR close to unity among smokers, and lower ORs suggested among never-smokers. For NAT2 slow versus rapid acetylator genotypes, the OR was 1.0 (95% CI, 0.6-1.5) overall, which broke down into an increased risk for slow acetylators among never-smokers but an increased risk for rapid acetylators among smokers. Among never-smokers, a gene interaction was suggested, with combined slow acetylator and GSTM1+ genotype conferring particularly high risk (OR = 3.1; 95% CI, 1.1-8.6), but no clear pattern emerged among smokers. A detailed analysis among smokers showed no interaction between pack-years of smoking and the GSTM1 genotype but suggested a steeper increase in risk with increasing pack-years of smoking exposure for rapid than for slow acetylators. Our results do not support a major role for the GSTM1 genetic polymorphism as a risk factor for lung cancer among smokers or nonsmokers. There was, however, some suggestion that the slow acetylator genotype may confer an increased risk among never-smokers and that the rapid acetylator genotype interacts with pack-year dose to produce a steeper risk gradient among smokers. 相似文献
20.
Characterization of the human class Mu glutathione S-transferase gene cluster and the GSTM1 deletion
A partial physical map has been constructed of the human class Mu glutathione S-transferase genes on chromosome 1p13.3. The glutathione S-transferase genes in this cluster are spaced about 20 kilobase pairs (kb) apart, and arranged as 5'-GSTM4-GSTM2-GSTM1-GSTM5-3'. This map has been used to localize the end points of the polymorphic GSTM1 deletion. The left repeated region is 5 kb downstream from the 3'-end of the GSTM2 gene and 5 kb upstream from the beginning of the GSTM1 gene; the right repeated region is 5 kb downstream from the 3'-end of the GSTM1 and 10 kb upstream from the 5'-end of the GSTM5 gene. The GSTM1-0 deletion produces a novel 7.4-kb HindIII fragment with the loss of 10.3- and 11.4-kb HindIII fragments. The same novel fragment was seen in 13 unrelated individuals (20 null alleles), suggesting that most GSTM1-0 deletions involve recombinations between the same two regions. We have cloned and sequenced the deletion junction that is produced at the GSTM1-null locus; the 5'- and 3'-flanking regions are more than 99% identical to each other and to the deletion junction sequence over 2.3 kb. Because of the high sequence identity between the left repeat, right repeat, and deletion junction regions, the crossing over cannot be localized within the 2.3-kb region. The 2.3-kb repeated region contains a reverse class IV Alu repetitive element near one end of the repeat. 相似文献